cRel and Wnt5a/Frizzled 5 Receptor-Mediated Inflammatory Regulation Reveal Novel Neuroprotectin D1 Targets for Neuroprotection

Abstract

Wnt5a triggers inflammatory responses and damage via NFkB/p65 in retinal pigment epithelial (RPE) cells undergoing uncompensated oxidative stress (UOS) and in experimental ischemic stroke. We found that Wnt5a-Clathrin-mediated uptake leads to NFkB/p65 activation and that Wnt5a is secreted in an exosome-independent fashion. We uncovered that docosahexaenoic acid (DHA) and its derivative, Neuroprotectin D1 (NPD1), upregulate c-Rel expression that, as a result, blunts Wnt5a abundance by competing with NFkB/p65 on the Wnt5a promoter A. Wnt5a increases in ischemic stroke penumbra and blood, while DHA reduces Wnt5a abundance with concomitant neuroprotection. Peptide inhibitor of Wnt5a binding, Box5, is also neuroprotective. DHA-decreased Wnt5a expression is concurrent with a drop in NFkB-driven inflammatory cytokine expression, revealing mechanisms after stroke, as in RPE cells exposed to UOS. Limiting the Wnt5a activity via Box5 reduces stroke size, suggesting neuroprotection pertinent to onset and progression of retinal degenerations and stroke consequences. Graphical Abstract NPD1 disrupts Wnt5a feedback loop at two sites: (1) decreasing FZD5, thus Wnt5a internalization, and (2) by enhancing cREL activity, which competes with p65/NFkB downstream endocytosis. As a result, Wnt5a expression is reduced, and so is its inflammatory signaling in RPE cells and neurons in ischemic stroke.

G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders

“… 591 FZD1 enhances myelin preservation and neuronal survival; 592 FZD3 is genetically related to substance-induced psychosis and schizophrenia; 593 , 594 Neuronal degeneration observed in amyotrophic lateral sclerosis is regulated by WNT5a/FZD4 signaling. 595 WNT5a/FZD5 activity is associated with neuronal inflammatory signaling; 596 Genetic FZD6 variants are associated with neural tube defects in the central nervous system; 597 FZD9 deletion is noted in patients with Williams-Beuren syndrome, a rare genetic disorder with mild to moderate intellectual disability or learning difficulties 598 FZD10 may play a role in brain vascular development; 599 SMO is the receptor for hedgehog proteins involved in neuronal/ glial proliferation and tissue regeneration. 600 …”

Investigation and validation of stereocilia development in homogenic cochlea progenitor cell organoid using bulk and single-cell RNA sequencing analysis

“…The most important consideration in modulating the differentiation process of inner ear organoids is the identi cation of optimal factors that can improve the e ciency of HC differentiation. During differentiation into inner ear HCs, Notch inhibition promotes the conversion of supporting cells into HCs 31,32 , while Wnt signaling in uences the proliferation and positioning of early HC precursors [33][34][35] .…”

Neuroprotective effects of a Wnt antagonist in quinolinic acid-induced excitotoxicity in N18D3 cells

“…Box5, a Wnt antagonist, is a Wnt5a-derived hexapeptide that is well known to antagonize Wnt5a-mediated cellular activities including, migration, invasion, calcium response, and MARCKS phosphorylation, effectively (9). In addition, Wnt5a is conserved in multiple species, including humans, mice, and rats, and Box5 has been shown to antagonize its effect via direct frizzled class receptor 5 (FZD5) binding (10).…”

“…This study concluded that the Wnt5a-JNK3 signaling pathway might be a new target for stroke therapy (11). Box5 also reduced stroke size, suggesting that decreasing FZD5 and enhancing p65/NFκB downstream endocytosis reduced Wnt5a expression and neuronal cell death (9). Given the protective effect of Box5 in neuronal death, we investigated whether Box5 protects neuronal cells from quinolinic acid (QUIN)-induced excitotoxicity by evaluating the mRNA expression levels of apoptosis-related genes.…”